ATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage

  • Nat Commun. 2018 Oct 8;9(1):4139. doi: 10.1038/s41467-018-06556-9.
Mingdong Liu  1 ,  Taoling Zeng  1 ,  Xin Zhang  1 ,  Chunyan Liu  1 ,  Zhihui Wu  1 ,  Luming Yao  1 ,  Changchuan Xie  1 ,  Hui Xia  1 ,  Qi Lin  1 ,  Liping Xie  1 ,  Dawang Zhou  1 ,  Xianming Deng  1 ,  Hong-Lin Chan  2 ,  Tong-Jin Zhao  3 ,  Hong-Rui Wang  4
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, 361102, China.
  • 2. Institute of Bioinformatics and Structural Biology, Department of Medical Sciences, National Tsing Hua University, Hsinchu, 30013, Taiwan.
  • 3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, 361102, China. [email protected].
  • 4. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Fujian, 361102, China. [email protected].
PMID: 30297842 DOI: 10.1038/s41467-018-06556-9
Abstract

DNA damage can induce autophagy; however, the underlying mechanism remains largely unknown. Here we report that DNA damage leads to Autophagy through ATR/Chk1/RhoB-mediated lysosomal recruitment of TSC complex and subsequent mTORC1 inhibition. DNA damage caused by ultraviolet light (UV) or alkylating agent methyl methanesulphonate (MMS) results in phosphorylation of small GTPase RhoB by Chk1. Phosphorylation of RhoB enhances its interaction with the TSC2, and promotes its sumoylation by PIAS1, which is required for RhoB/TSC complex to translocate to lysosomes. As a result, mTORC1 is inhibited, and Autophagy is activated. Knockout of RhoB severely attenuates lysosomal translocation of TSC complex and the DNA damage-induced Autophagy. Reintroducing wild-type but not sumoylation-resistant RhoB into RhoB-/- cells restores the onset of Autophagy. Hence, our study identifies a molecular mechanism for translocation of TSC complex to lysosomes in response to DNA damage, which depends on ATR/Chk1-mediated RhoB phosphorylation and sumoylation.

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